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Novel Diacylglycerol Acyltransferase-1 (DGAT-1) Inhibitor..1-(4-(4-Amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl)cyclobutanecarbonitrile
C19 H19 N5 O2
|Inventores||Gary E. Aspnes, Robert L. Dow, Michael J. Munchhof|
|Beneficiário Original||Pfizer Inc|
Enzyme acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the rate-limiting step in triglyceride synthesis. It has recently emerged as an attractive target for therapeutic intervention in the treatment of Type II diabetes and obesity.
It is estimated that somewhere between 34 and 61 million people in the US are obese and, in much of the developing world, incidence is increasing by about 1% per year. Obesity increases the likelihood of death from all causes by 20%, and more specifically, death from coronary artery disease and stroke are increased by 25% and 10%, respectively. Key priorities of anti-obesity treatments are to reduce food intake and/or hyperlipidemia. Since the latter has been suggested to provoke insulin resistance, molecules developed to prevent the accumulation of triglyceride would not only reduce obesity but they would also have the additional effect of reducing insulin resistance, a primary factor contributing to the development of diabetes. The therapeutic activity of leptin agonists has come under scrutiny through their potential to reduce food intake and, also, to reverse insulin resistance; however, their potential may be compromised by leptin-resistance, a characteristic of obesity. Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT-1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis and an enzyme that is tightly implicated in both the development of obesity and insulin resistance. DGAT-1 deficient mice are resistant to diet-induced obesity through a mechanism involving increased energy expenditure. US researchers have now shown that these mice have decreased levels of tissue triglycerides, as well as increased sensitivity to insulin and to leptin. Importantly, DGAT-1 deficiency protects against insulin resistance and obesity in agouti yellow mice, a model of severe leptin resistance. Thus, DGAT-1 may represent a useful target for the treatment of insulin and leptin resistance and hence human obesity and diabetes. Chen, H. C., et al., J Clin Invest, 109(8), 1049-55 (2002).
Although studies show that DGAT-1 inhibition is useful for treating obesity and diabetes, there remains a need for DGAT-1 inhibitors that have efficacy for the treatment of metabolic disorders (e.g., obesity, Type 2 diabetes, and insulin resistance syndrome (also referred to as “metabolic syndrome”)).
Scheme II outlines the general procedures one could use to provide compounds of the general Formula (II).
Scheme IV outlines a general procedure for the preparation of compounds of the general Formula VI.
1-[4-(4-amino-2-methoxy-5-oxo-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)phenyl]cyclobutanecarbonitrilePotassium nitrate (7.88 g, 77.0 mmol) was suspended in sulfuric acid (45 mL) at 0° C. and stirred for 30 minutes until a clear and colorless solution was obtained (NOTE—a blast shield is highly recommended). An addition funnel was charged with 1-phenylcyclobutanecarbonitrile (11.40 g, 72.5 mmol), and this neat starting material was added drop wise at such a rate that the internal reaction temperature did not exceed 10° C. Upon completion of the addition (which required 90 min), the mixture was poured onto 300 g of ice and stirred vigorously for 30 minutes. The resulting suspension was filtered, and the solid was washed with water and dried under vacuum to afford give 1-(4-nitrophenyl)cyclobutanecarbonitrile (13.53 g, 92%) as a light tan powder.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 2.11-2.21 (m, 1H) 2.47-2.58 (m, 1H) 2.66 (s, 2H) 2.88-2.96 (m, 2H) 7.63 (d, J=8.54 Hz, 2H) 8.29 (d, J=8.54 Hz, 2H).
A steel hydrogenation vessel was loaded with 1-(4-nitrophenyl)cyclobutanecarbonitrile (103.6 g, 0.51 mol), 10% palladium on activated carbon (10.3 g; contains ˜50% of water), and 2-methyltetrahydrofuran (1.3 L). The mixture was stirred under 30 psi of hydrogen gas at 45° C. for 4 h. The mixture was filtered through a pad of celite and filtrate concentrated. Heptane (1 L) was added to the obtained oil and the heterogeneous mixture was stirred while slowly cooled to room temperature, causing the product aniline to solidify. The solid was filtered off and dried in vacuum to give 1-(4-aminophenyl)cyclobutanecarbonitrile (86.6 g, 98%).
1H NMR (CHLOROFORM-d) δ ppm 7.12-7.25 (m, 2H), 6.61-6.76 (m, 2H), 3.68 (br. s., 2H), 2.68-2.88 (m, 2H), 2.48-2.64 (m, 2H), 2.30-2.45 (m, 1H), 1.94-2.14 (m, 1H)
A mixture of 1-(4-aminophenyl)cyclobutanecarbonitrile (42.2 g, 245 mmol), triethylamine (27.1 mL, 394 mmol), and ethyl acrylate (28.0 mL, 258 mmol) were combined in ethanol (27 mL) and heated to reflux for 24 hours. The mixture was concentrated to dryness and toluene (600 mL) added and concentrated to dryness to give ethyl N-[4-(1-cyanocyclobutyl)phenyl]beta-alaninate as brown oil, which was used without further purification.
1H NMR (CHLOROFORM-d) δ ppm 7.22 (d, 2H), 6.63 (d, 2H), 4.12-4.21 (m, 3H), 3.47 (q, J=6.3 Hz, 2H), 2.74-2.83 (m, 2H), 2.53-2.66 (m, 4H), 2.33-2.45 (m, 1H), 2.00-2.11 (m, 1H), 1.28 (t, 3H)
Ethyl N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate was combined with cyanoacetic acid (22.9 g, 270 mmol) and 4-dimethylaminopyridine (2.30 g, 18.8 mmol) in N,N-dimethylformamide (400 mL) and cooled to 0° C. Diisopropylcarbodiimide (41.7 mL, 270 mmol) was then added drop wise over 30 minutes. Once addition was complete, the reaction was slowly warmed up to room temperature and stirred for 16 hours. Reaction was then poured into saturated aqueous sodium bicarbonate (600 mL) and stirred for 30 mintues. Ethyl acetate (1 L) was added and the mixture was filtered to remove the insoluble diisopropylurea. The phases of the filtrate were separated, and the organic phase was washed with brine and dried over sodium sulfate and concentrated to give ethyl N-(cyanoacetyl)-N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate as yellow oil that was used with out further purification in the following step.
ethyl N-(cyanoacetyl)-N-[4-(1-cyanocyclobutyl)phenyl]-beta-alaninate and 1,8-diazabicyclo[5.4.0]undec-7-ene (350 mmol) were combined in methanol (400 mL) and heated to 70° C. for 30 minutes. The mixture was concentrated to dryness then partitioned between water (400 mL) and 2:1 ethyl acetate:heptane (400 mL). The aqueous phase was separated and acidified to pH 2 by the addition of 1M hydrochloric acid (400 mL). The precipitate was filtered off and washed with water (300 mL) and 2:1 ethyl acetate:heptane (300 mL) give 1-(4-(1-cyanocyclobutyl)phenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (31.7 g, 44% over 3 steps) as an off-white solid.
1H NMR (DMSO-d6) δ ppm 7.39-7.45 (m, 2H), 7.31 (d, 2H), 3.78 (t, J=6.7 Hz, 2H), 2.79 (t, 2H), 2.66-2.75 (m, 2H), 2.53-2.64 (m, 2H), 2.16-2.31 (m, 1H), 1.91-2.04 (m, 1H)
1-(4-(1-Cyanocyclobutyl)phenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (50.0 g, 170 mmol) and N,N-dimethylformamide (0.66 mL, 8.5 mmol) in dichloromethane (350 mL) was cooled to 0° C. Oxalyl chloride (18.0 mL, 203 mmol) was added over 15 minutes. The mixture was warmed to room temperature over 2 hours. Methanol (300 mL) was then added as a steady stream, and the mixture was heated at 45° C. for 16 hours. The mixture was cooled to room temperature and concentrated to get rid of most of the dichloromethane. Methanol (200 mL) was added and the thick slurry was stirred for 2 hours. The solid was filtered and dried under vacuum to give 1-(4-(1-cyanocyclobutyl)phenyl)-4-methoxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (48.3 g, 92%) as an off-white powder.
1H NMR (400 MHz, DMSO-d6) δ ppm 1.91-2.03 (m, 1H) 2.18-2.31 (m, 1H) 2.54-2.63 (m, 2H) 2.67-2.75 (m, 2H) 3.03 (t, J=6.73 Hz, 2H) 3.85 (t, J=6.73 Hz, 2H) 4.01 (s, 3H) 7.33 (d, J=8.78 Hz, 2H) 7.44 (d, J=8.78 Hz, 2H)
1-(4-(1-Cyanocyclobutyl)phenyl)-4-methoxy-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile (12.04 g, 37.9 mmol) and cyanamide (1.64 g, 41.0 mmol) were suspended in methanol (200 mL) at room temperature. A solution of 25% sodium methoxide in methanol (45.0 mmol) was then added drop wise over 10 minutes to obtain a clear homogeneous solution of the intermediate cyanamide adduct. In one portion, sulfuric acid (5.06 mL, 94.9 mmol) was added, and the mixture was heated to 50° C. for 16 hours. The mixture was then cooled to room temperature and basified to pH 10-11 by the addition of 1N sodium hydroxide, and the thick suspension was stirred for 20 minutes. The solid was filtered, washed with cold methanol and water, and dried under vacuum to obtain the crude product as a mixture contaminated with the vinylogous amide (4-amino-1-[4-(1-cyanocyclobutyl)phenyl]-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile). This solid mixture was heated to reflux in methanol (150 mL) for 3 hours then cooled to room temperature and filtered. The solid collected was then dissolved in a minimal amount of acetic acid (30 mL) at 60° C. to obtain a clear yellow solution. Water was then added drop wise at 60° C. until the cloudiness persisted, and the mixture was allowed to return to room temperature. Another 50 mL of water was added and the fine suspension was filtered, washed with water, and dried under vacuum to afford the title compound (4A) (6.80 g, 51%) as a light yellow solid.
1H NMR (500 MHz, DMSO-d6) δ ppm 1.97-2.06 (m, 1H) 2.23-2.34 (m, 1H) 2.59-2.67 (m, 2H) 2.71-2.79 (m, 2H) 2.96 (t, J=6.71 Hz, 2H) 3.86 (s, 3H) 3.91 (t, J=6.71 Hz, 2H) 7.39-7.44 (d, J=8.54, 2H) 7.47-7.51 (d, J=8.54, 2H) 7.81 (br. s., 1H) 8.35 (br. s., 1H).
(a) Birch, A. M.; Buckett, L. K.; Turnbull, A. V. Opin. Drug Discovery Dev. 2010, 13,489(b) Zammit, V. A.; Buckett, L. K.; Turnbull, A. V.; Wure, H. Pharmacol. Ther. 2008, 118, 295
(a) Dow, R. L.; Munchhof, M. J. U.S. Patent Appl.2010/0197590.(b) Aspnes, G. E.; Dow, R. L.; Munchhof, M. J. U.S. Patent Appl. 2010/0197591.(c) Bahnck, K. B.; Shavnya, A.; Tao,Y.; Lilley, S. C.; Andrews, M. P.; Aspnes, G. E.; Bernhardson, D. J.; Bill, D. R.; Bundesmann, M. W.; Dow, R. L.; Karki, K.; Le, T.; Li, Q.; Munchhof, M. J.; Nematalla, A.; Nihlawi, M.; Patel, L.; Perreault, C.; Waldo, M. Synthesis 2012, 44, 3152
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Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, D.C.: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).
Another aspect of the invention is for the treatment or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin-dependent diabetes mellitus, also referred to as “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as “NIDDM”) diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications (such as atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).
Yet another aspect of the invention is the treatment of diabetes- or obesity-related co-morbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, hypertension, insulin resistance, diabetes (e.g., Type 2 diabetes), weight gain, coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., “The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth —Where Does the International Diabetes Federation Stand?,” Diabetes & Endocrinology, 7(2), (2005); and Alberti, K. G., et al., “The Metabolic Syndrome —A New Worldwide Definition,” Lancet, 366, 1059-62 (2005). Administration of the compounds of the invention may provide a statistically significant (p<0.05) reduction in at least one cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive protein (CRP) and/or cholesterol, as compared to a vehicle control containing no drug. The administration of compounds of the invention may also provide a statistically significant (p<0.05) reduction in glucose serum levels.
In yet another aspect of the invention, the condition treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and diabetic cardiomyopathy, anorexia nervosa, bulimia, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart failure, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung cancer, colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer.anti-obesity agent is selected from the group consisting of dirlotapide, mitratapide, implitapide, R56918 (CAS No. 403987), CAS No. 913541-47-6, lorcaserin, cetilistat, PYY3-36, naltrexone, oleoyl-estrone, obinepitide, pramlintide, tesofensine, leptin, liraglutide, bromocriptine, orlistat, exenatide, AOD-9604 (CAS No. 221231-10-3) and sibutramine; and said anti-diabetic agent is selected from the group consisting of metformin, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, tolbutamide, tendamistat, trestatin, acarbose, adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, salbostatin, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone, troglitazone, exendin-3, exendin-4, trodusquemine, reservatrol, hyrtiosal extract, sitagliptin, vildagliptin, alogliptin and saxagliptin.Exemplary anti-obesity agents for use in the combination aspects of the invention include gut-selective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. 403987) and CAS No. 913541-47-6), CCKa agonists (e.g., N-benzyl-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10 b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide described in PCT Publication No. WO 2005/116034 or US Publication No. 2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in U.S. Pat. No. 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY3-36(as used herein “PYY3-36” includes analogs, such as peglated PYY3-36 e.g., those described in US Publication 2006/0178501), opioid antagonists (e.g., naltrexone), oleoyl-estrone (CAS No. 180003-17-2), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine